Project Summary Significance: Since 2013 avian influenza A (H7N9) has sickened over 1500 people with a 39% mortality rate. Half of all cases occurred in 2017 which also saw the emergence of a highly pathogenic strain. Thus, H7N9 avian influenza is poised to emerge as a devastating pandemic in a worldwide population that has no pre-existing immunity. Current H7 vaccines, whether attenuated, inactivated, split or recombinant, are insufficiently immunogenic in people. Addition of adjuvants including squalene emulsions or alum can improve the immunogenicity of H7 vaccines, but these adjuvanted vaccines still require two immunizations to achieve protective antibody titers and these responses are not durable. Additionally, it is unknown if these adjuvanted vaccines provide sufficient breadth of immunity to be effective against the antigenically drifted H7 strains which have begun to appear. Thus there is an urgent need to develop a more effective and safe adjuvant for H7 influenza vaccines to meet these shortcomings. Improving the adjuvanticity of a clinically approved alum adjuvant by optimizing its structure and composition is an under-explored solution to this important challenge. Innovation: The physical properties of adjuvants affect their ability to induce a robust immune response. For example, reducing the particle size of alum from ~0.5 to 10 m to 80-400 nm generates a stronger immune response while decreasing injection site inflammation. Additionally, surface charge affects adjuvant uptake in vivo and determines the binding affinity of vaccine antigens to alum. We have taken advantage of this knowledge to generate an exciting new class of adjuvants - stable and well-defined aluminum nanoparticles (nanoalum) - using a unique and scalable method to produce stable nanoparticles from the clinically approved alum. A prototype nanoalum demonstrates superior adjuvant activity compared to Alhydrogel and augments the efficacy of an experimental flu vaccine. Specific Aims: In Phase I of this SBIR we will complete two specific aims: (1) synthesize stable nanoalum formulations that are compatible with an H7 VLP antigen and (2) identify the nanoalum properties that augment the safe and durable protective immunity to H7N9 viruses. In Phase II will complete preclinical efficacy and safety testing, process development, and GMP manufacture in preparation for clinical testing.